{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:11:21Z","timestamp":1792793481433,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centro Ames"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and\/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid\/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification.<\/jats:p>","DOI":"10.3390\/cancers18060994","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:49:24Z","timestamp":1773924564000},"page":"994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polyploid and Chromosomal Copy Number Gain Cells in Metastatic Colon Cancer: Exploratory Genotype\u2013Phenotype Correlations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-3855","authenticated-orcid":false,"given":"Alessandro","family":"Ottaiano","sequence":"first","affiliation":[{"name":"SSD-Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori di Napoli, IRCCS \u201cG. Pascale\u201d, Via M. Semmola, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Zito Marino","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Ianniello","sequence":"additional","affiliation":[{"name":"Centro AMES, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-3126","authenticated-orcid":false,"given":"Giuliana","family":"Ciappina","sequence":"additional","affiliation":[{"name":"Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2362-764X","authenticated-orcid":false,"given":"Enrica","family":"Toscano","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, \u201cG. Martino\u201d Hospital, Viale Gazzi, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-3572","authenticated-orcid":false,"given":"Antonio","family":"Ieni","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"},{"name":"Division of Pathology, \u201cG. Martino\u201d Hospital, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Luc\u00e0","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Sirica","sequence":"additional","affiliation":[{"name":"Centro AMES, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica","family":"Maiorana","sequence":"additional","affiliation":[{"name":"School of Specialization in Medical Oncology, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Berretta","sequence":"additional","affiliation":[{"name":"Department of Human Pathology \u201cG. Barresi\u201d, \u201cG. Martino\u201d University Hospital, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Di Carluccio","sequence":"additional","affiliation":[{"name":"Department of Economics, University of Foggia, 71121 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-6091","authenticated-orcid":false,"given":"Michele","family":"Caraglia","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi De Crecchio 7, 80138 Naples, Italy"},{"name":"Laboratory of Precision and Molecular Oncology, Biogem scarl, 83031 Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5274-3989","authenticated-orcid":false,"given":"Giovanni","family":"Savarese","sequence":"additional","affiliation":[{"name":"Centro AMES, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Franco","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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